1-hydrocarbon-3-aryl-4-subsituted ethyl-2-imidazolidinones



United States Patent Oflice Patented Feb. 25, 1969 3,429,893l-HYDROCARBON-3-ARYL-4-SUBSITUTED ETHYL-Z-IMIDAZOLIDINONES Carl D.Lunsford, Richmond, and Albert D. Cale, Jr.,

Bon Air, Va., assignors to A. H. Robins Company, Incorporated, Richmond,Va., a corporation of Virginia No Drawing. Original application Dec. 31,1964, Ser. No. 422,570, now Patent No. 3,337,580, dated Aug. 22, 1967.Divided and this application Dec. 28, 1966, Ser. No. 605,183 US. Cl.260-309.7 Int. Cl. C07d 49/30; A61k 27/00 7 Claims ABSTRACT OF THEDISCLOSURE 1 hydrocarbon 3 aryl 4 substituted ethyl 2- imidazolidinoneswherein the substituent on the 4-ethyl group is cyano, carb-lower-alkoxyor carbamyl. The compounds are useful as analeptics,

The present application is a division of our prior-filed copendingapplication Ser. No. 422,570, filed Dec. 31, 1964, now US. Patent3,337,580, issued Aug. 22, 1967.

The present invention relates to certain novel heterocyclic organiccompounds which may be referred to as substituted Z-imidazolidinones,and is more particularly concerned with1,3-disubstituted-4-(2-substituted-ethyl)- Z-imidazolidinones,compositions thereof, and methods of making and using the same.

The invention is especially concerned with novel imidazolidinonecompounds having the formula:

wherein carb-lower-alkoxy, carbamyl, and amino.

The compounds of the invention having the foregoing Formula I aregenerally characterized by important pharmacological activity,indicative of their use in counteracting certain physiologicalabnormalities in an animal body. The compounds are analeptics,hypotensives, or both. Certain compounds of the series are potentanaleptics, stimulating respiration and antagonizing central nervoussystem depression and exhibiting a particular antagonism againstbarbiturate-induced depression or poisoning at dose levels considerablybelow that at which untoward side effects occur. In addition, as will beapparent and become more obvious hereinafter, some compounds, eventhough active in themselves, are also valuable as intermediates inpreparing other and still more active compounds of Formula I, e.g.,p-haloethyl (or 2-haloethyl) compounds, the fi-carboxyethyl (or2-carboxyethyl) compounds, and the like. Those compounds having areactive functional group in the side-chain are of course useful, asshown herein, as reactants in standardtype reactions characteristic ofthe functional group contained therein, While the degree and relativedegree of their activities vary, all compounds tested exhibitedanaleptic activity, although, as stated, because of the relative degreeof activity, some are preferred as hypotensives. The salts have specialutility in that they are watersoluble and have an extended duration ofactivity.

The activity of the active agents of the present invention, as evidencedby tests in lower animals, is indicative of utility based on theirvaluable activity.

It is accordingly an object of the present invention to provide new anduseful 1,3-disubstituted-4-(Z-substituted-ethyl)2-irnidazo1idinones,compositions thereof, and methods of making and using the same. Otherobjects of the invention will be apparent to one skilled in the art, andstill other objects will become apparent hereinafter.

In the definition of symbols in the foregoing Formula I and where theyappear elsewhere throughout this specification, the terms have thefollowing significance.

The term lower-alkyl as used herein includes straight and branched chainradicals of up to eight carbon atoms inclusive and is exemplified bysuch groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl,isoamyl, hexyl, heptyl, octyl, and the like. Lower alkoxy has theformula-O-lower-alkyl. The term lower-alkeny includes straight andbranched chain radicals of two up to eight carbon atoms inclusive and isexemplified by such groups as vinyl, allyl, methallyl, 4-pentenyl,3-hexenyl, and 3-methyl-3-heptenyl. The term cycloalkyl as used hereinincludes primarily cyclic alkyl radicals containing three up to ninecarbon atoms inclusive and encompasses such groups as cyclopropyl,cyclobutyl, cyclohexyl, cyclopentyl, methylcyclohexyl, propylcyclohexyl,ethylcyclopentyl, propylcyclopentyl, dimethylcyclohexyl, cycloheptyl,and cyclooctyl. The term cycloalkenyl as used herein includes cyclicalkenyl radicals containing up to nine carbon atoms inclusive andencompasses the named cycloalkyl radicals having one or more doublebonds, including such usual radicals as 1- and 2-cyclohexenyl and land2-cyclopentenyl. Included in the term phenyllower-alkyl are groups suchas benzyl, phenethyl, methylbenzyl, phenpropyl, and the like. As stated,the radical R in the foregoing Formula -I is inclusive of such groups aslower-alkyl, cycloalkyl, cycloalkenyl, and phenyllower-alkyl, whichgroups are all preferably radicals of a solely hydrocarbon nature.

When halogen is referred to herein, preferably but not necessarily ahalogen of atomic weight in excess of nineteen but not greater thaneighty is employed. 0f the halogens, chlorine is preferred.

Among the suitable amino radicals included within the symbol R" areprimary, secondary and tertiary amino radicals, such as unsubstitutedamino (-NH loweralkyl-amino; di'lower-alkylamino; lower-alkenyl-amino;di-lower-alkenyl-amino; phenylamino; (hydroxy-loweralkyl)-amino;di-(hydroxy-lower-alkyl)-amino; loweralkyl-(hydroxy-lower-alkyl) amino;basic saturated monocyclic heterocyclic radicals having up to a maximumof twelve carbon atoms, as exemplified by piperidino;lower-alkyl-piperidino, e.g., 2-, 3-, or 4-lower-alkyl piperidino;di-lower-alkyl-piperidino; e.g., 2,4-, 2,6-, or3,5-di-lower-alkyl-piperidino; lower alkoxy-piperidino; pyrrolidino;lower-alkyl pyrrolidino; di-lower-alkylpyrrolidino;lower-alkoxy-pyrrolidino; morpholino; loweralkyl-morpholino;dilower-alkyl morpholino; loweralkoxy-morpholino; thiomorpholino;lower-alkyl-thiomorpholino; di-lower-alkyl-thiomorpholino;lower-alkoxythiomorpholino; piperazino; lo-wer-alkyl-piperazino (e.g.,C- or N -methylpiperazino); di-C-(lower-alkyl)piperazino; N-(lower-alkyl)-C-(lower-alkyl)-piperazino; N-

3 (hydroxy-lower-alkyl) piperazino; N-(lower-aliphatic acyloxy) and(especially lower-alkanoyloxy lower-alkyl)- piperazino [e.g.,N-(acetoxy-, isobutyroxy-, or octanoyloxyethyl or propyl) -piperazino];lower-alkoxy-piperazino; N-lower-alkoxy)-lower-alkylpiperazino, e.g.,N-ethoxyethylpiperazino; and lower-carbalkoxy-piperazino.

Included with the scope of -N-(lower-alkanoyl)- amino are thecorresponding tertiary amino radicals designated-N-(lower-alkanoyl)-N-lower-alkylamino. The term carbamyl encompassesnot only the primary amino-containing carbamyl radicals, but also thecorresponding N-phenyland N-(lower-alkyl)-carbamyl andN,N-di-(lower-alkyl)-carbamyl radicals as well as the correspondingN,N-diphenyllower-alkyl, N,N-monocyclic alkyl, and saturatedheterocyclic carbamyl radicals, wherein the saturated monocyclicheterocyclic radical is as set forth under the definition of amino inthe foregoing. The amino moiety of the carbamyl radical is additionallyvariable in accord with the definition of amino previously given.

Among the suitable substituted phenyl radicals are phenyl radicalssubstituted by any radical or radicals which are not reactive orotherwise interfering under the conditions of reaction, such aslower-alkoxy, loweralkylmercapto, lower-alkyl, di-lower-alkyl-amino,trifiuoromethyl, halo, and the like. The substituted-phenyl radicalshave preferably no more than one to three substituents such as thosegiven above and, furthermore, these substituents can be in variousavailble positions of the phenyl nucleus and, when more than onesubstituent is present, can be the same or different and can be invarious position combinations relative to each other. The lower-alkyl,loWer-alkoxy, lower-alkylmercapto, and di-lower-alkyl-amino substituentseach have preferably from one to four carbon atoms which can be arrangedas straight or branched chains. A total of nine carbon atoms in all ringsubstiutents is the preferred maximum.

When R is amino, the compounds of Formula I may be converted to and aremost conveniently employed in the form of non-toxic pharmaceuticallyacceptable acid addition or quaternary ammonuim salts. Such salts alsohave improved water-solubility. Although the non-toxic salts arepreferred, any salt may be prepared for use as a chemical intermediate,as in the preparation of another but non-toxic acid addition salt. Thefree basic compounds of Formula I may be conveniently converted to theirquaternary ammonium or acid addition salts by reaction of the free basewith the selected acid or acid ester, e.g., an alkyl, cycloalkyl,alkenyl, cycloalkenyl or aralkyl halide, sulfate, or sulfonate,preferably in the presence of an organic solvent inert to the reactantsand reaction products under the conditions of the reaction. The acidswhich can be used to prepare the preferred non-toxic acid addition saltsare those which produce, when combined with the free bases, salts theanions of which are relatively innocuous to the animal organism intherapeutic doses of the salts, so that beneficial physiologicalproperties inherent in the free bases are not vitiated by side-effectsascribable to the anions.

Appropriate acid addition salts are those derived from mineral acidssuch as hydrochloric acid, hydrobromic acid, hydriodic acid, nitricacid, sulfuric acid, and phosphoric acid; and organic acids such asacetic acid, citric acid, lactic acid, fumaric acid, and tartaric acid.The preferred acid addition salt is the hydrochloride. The quaternaryammonium salts are obtained, e.g., by the addition of alkyl, cycloalkyl,alkenyl, cycloalkenyl, or aralkyl esters of inorganic acids or organicsulfonic acids, to the free base form of the selected tertiary aminocompound. The alkyl, cycloalkyl, alkenyl, cycloalkenyl, or aralkylesters so used include such compounds as methyl chloride, methylbromide, methyl iodide, ethyl bromide, propyl chloride, allyl chloride,allyl bromide, dimethyl sulfate, methyl benzene sulfonate, methylp-toluene sulfonate, benzyl halides such as p-chlorobenzy chloride andp-nitrobenzyl chloride, and the like.

The acid addition salts are prepared either by dissolving the free basein an aqueous solution containing the appropriate acid and isolating thesalt by evaporating the solution, or by reacting the free base and theselected acid in an organic solvent, in which case the salt ordinarilyseparates directly or can be conventionally recovered by concentrationof the solution or the like. Conversely the free base may be obtainedconventionally by neutralizing the acid addition salt with anappropriate base such as ammonia, ammonium hydroxide, sodium carbonateor the like, extracting the liberated base with a suitable solvent,illustratively ethyl acetate or benzene, drying the extract andevaporating to dryness or fractionally distilling, or in otherconventional manner.

When there are two or more basic nitrogen atoms present in the compoundsof the invention, poly-acidaddition salts may be obtained by employingthe proper increased molar ratios of acid to the free base.

The following Chart 1 illustrates the process of the invention and showsthe various procedures involved both in preparing the starting materialsand the final products of the invention. In Chart I, all the symbolshave the values previously assigned.

imidazolidinone ring formation (note c) (R,R' and R" have valuespreviously assigned) (X is halogen, preferably chlorine) (P is an alkylor aryl group) Notes:

The starting materials for the process of the present invention are theappropriately substituted 3 aminopyrrolidines, represented in Chart I byFormula IV. These materials (IV) may in turn be obtained from a 1substituted 3 pyrrolidinol, shown as Formula 11.

As illustrated in the chart, a l substituted 3 pyrrolidinol (II) isconverted to a 1 substituted 3 haloor 3 alkylsulfonyloxy or 3arylsulfonyloxy pyrrolidine (III) by reaction with an agent such asthionyl chloride or bromide, or an alkylor aryl-sulfonyl halide, andallowing the thus-formed 3-haloor 3 sulfonyloxypyrrolidine to react witha primary amine to produce a compound of Formula IV, the startingmaterial of the present invention.

As a general procedure for preparing the starting materials (IV), asuspension of sodamide in an appropriate solvent, e.g., dry toluene, isplaced in a suitable reaction vessel, such as a three-liter three-neckedround-bottomed flask equipped with stirrer, reflux condenser,thermometer and dropping funnel. The dispersion is maintained at asuitable temperature, generally less than about 50 C., during thedropwise addition of a 1 substituted 3- pyrrolidinol to the reactiOnmedium. A solution of an arylsulfonyl halide is then added to thereaction mixture while maintaining a reduced temperature, e.g., about-10 C. Arylsulfonyl halides such as p-toluenesulfonyl chloride andbenzene-sulfonyl chloride in toluene solution may be employed in theformation of the desired sulfonates. Stirring of the reaction mixturesis continued for an additional period, generally about two hours, whileallowing the temperature to rise slowly to about 30 C. The reactionmixture is then washed several times with cold water to remove anyremaining unreacted reactants. The toluene extract containing thepyrrolidine-3- sulfonate is dried with a suitable drying agent such ascalcium sulfate. After removal of the drying agent, the toluene may beremoved by evaporation and the residual sulfonate allowed to react witha primary arylamine, which is preferably employed in excess. Thearylamine is added to the sulfonate and the temperature raised to alevel of about ISO-175 C. for an extended period, such as five to tenhours. The length of time and temperature required for the reaction aredependent upon the type of arylamine used in a particular preparation.On termination of the heating or reflux period, any unreacted arylaminemay be removed under reduced pressure (as by water aspirator vacuum) andthe remaining concentrated residue may be neutralized with an acid suchas cold dilute hydrochloric acid. The resulting aqueous solution of thesalt, e.g., the hydrochloride, of the desired base may then beneutralized with a strong caustic solution (as for example 50% aqueoussodium hydroxide) to yield the free aminopyrrolidine base. The free basemay be separated by extraction with ether and dried in the usual manner(i.e., with calcium sulfate). The product may be isolated and purifiedby distillation under reduced pressure. In some preparations, the freebases may be advantageously converted to their acid addition salts,e.g., the fumarate or cyclohexylsulfamate salt.

The following preparations are given by way of illustration only and arenot to be construed as limiting.

Preparation 1.l-methyl-3-anilinopyrrolidine A dry toluene (1 liter)suspension of sodamide (2 moles) was placed in a 3-liter, B-necked,round-bottomed flask equipped with a stirrer, reflux condenser,thermometer and dropping funnel. While maintaining the dispersion at atemperature of l540 C., 1-methyl-3-pyrrolidinol (2 moles) was addeddropwise. On completing the addition of the pyrrolidinol, the reactionmixture was stirred for two hours, gradually lowering the temperature to10 C. A dry toluene (1 liter) solution of p-toluenesulfonyl chloride (2moles) was added dropwise maintaining the temperature at less than 20 C.The reaction mixture was stirred for two hours at 20-30 C. and thenwashed with cold water (2X 500 ml.). The toluene extract was dried overanhydrous calcium sulfate (Drierite). After removal of the drying agent,the toluene was removed by evaporation and the concentrated tosylate wasallowed to react with aniline (4.4 moles, 10% excess). Reaction of theaniline with the tosylate [(1-methyl-3- pyrrolidyl)-p-toluenesulfonate]was effected by heating at C. for two hours and then raising thetemperature to reflux and heating for an additional three hours. Theexcess unreacted aniline was removed under reduced pressure (wateraspirator vacuum) and the remaining residue treated with a suificientamount of cold dilute hydrochloric acid to effect solution. The acidsolution was extracted several times with ethyl ether, cooled, and madebasic with 50% aqueous sodium hydroxide. The free base was removed byextraction with ether. The ether extracts were washed with water anddried over Drierite (anhydrous calcium sulfate). The drying agent wasremoved by filtration and the ether removed under reduced pressure. Theresultant residue was then distilled at reduced pressure, B.P. 124126 C.at 4 mm. pressure. The product was obtained in 52% yield. Thecorresponding fumarate salt was obtained from dry isopropanol solvent,M.P. 143144 C.

Analysis.Calculated for C H N O C, 61.63; H, 6.90; N, 9.58 (fumaratesalt). Found: C, 61.58; H, 7.07; N, 9.47.

tion with one exception, the p-toluenesulfonyl chloride was replacedwith benzenesulfonyl chloride (in a toluene solution). The resultant (1-phenethyl-3-pyrrolidyl)benzenesulfonate (0.11 mole) was mixed withaniline (0.40 mole) and the mixture heated with stirring for two hoursat 150 C. and then at reflux for three additional hours. The excessunreacted aniline was then distilled at reduced pressure and the residuedissolved in dilute hydrochloric acid. The acidic solution was extractedwith ether and then made basic with aqueous sodium hydroxide. The freebase which separated was extracted With ether TABLE l.-PREPARATIONS 2THROUGH 12 Preparation Arylaminopyrrolidine Boiling Pressure Yield,

Number R R Point, C. (nun/Hg) percent Remarks 2 CH3 Q 94-6 0.15 12Fumarate 129-130 0.

3 0211. our. 131-0 4 es Fumarate103104 o.

4 C2115 CIQ- 113-5 005 5 C2115 OH3O 128-30 0.15 36 e 02H: omQ- 102-3 25Fumarate lee-150.5 o

7 among 01H. 140-3 4 42 Fumarate132-134" o.

s omens 102-0 0.1 40 Fumarate 158-159 0.

l CH3 0 among). Q- 120-5 0. 0s 41 Fumarate 105-100" 0.

l C1 CH;

10 O- Q- 135-8 0. 05 01 Fumarate res-191 0.

11 Q-on; 06H, 160-4 0.01 40 Fumarate 130-140.? 0.

12 01H; 14550 0. 05 46 Fumarate 612-163 0.

TABLE IL-ANALYTICAL DATA ON PREPARATIONS 2 THROUGH 12 CalculatedEmpirical Found Prepara- Formula 12 C20H24N204 l Fumarate salts.

Preparation 13.--1-phenethyl-3-anilinopyrrolidine The same generalmethod employed in the preparation of the tosylate in Preparation 1 wasused in this prepara- Preparation14.1-ethyl-3-(m-trifiuoromethylanilino) pyrrolidineN-cyclohexylsulfamate Utilizing the procedure described in Preparation13, (1- ethyl-3-pyrrolidyl)benzenesulfonate was heated and reacted withm-trifluoromethylaniline to produce 1-ethyl-3-(m-trifluoromethylanilino)pyrrolidine in 23% yield. Preparation of thecyclohexylsulfamate salt was accomplished by neutralization of the freebase with cyclohexylsulfamic 9 acid in isopropanol solvent. The productwas precipitated by the addition of isooctane, M.P. l-116 C.

Analysis.Calculated for C H F N O S: C, 52.16; H, 6.91; N, 9.60. Found:C, 52.27; H, 7.04; N, 9.65.

Preparation 15 .1 l-cyclohexenyl) -3-anilinopyrrolidine Using the methoddescribed in Preparation 13, [1-(1-cyclohexenyl)-3-pyrrolidyl]benzenesulfonate is prepared and reacted withaniline to produce 1-(1-cyclohexenyl)- 3-anilinopyrrolidine. The2-cyclohexenyl compound may be prepared similarly by using theappropriate 2-cyclohexenyl starting compound.

Preparation l6.1-allyl-3-anilinopyrrolidine Using the method ofPreparation 13, (1-allyl-3-pyrrolidyl)-benzenesulfonate is prepared andreacted with aniline to form 1-allyl-3-anilinopyrrolidine.

Preparation l7.--1-methyl-3-(2-methylmercaptoanilino) pyrrolidine Usingthe method of Preparation 13, (1-methyl-3-pyrrolidyl) -benzenesulfonateis prepared and reacted with 2- methylmercaptoaniline to forml-methyl-3-(2-methylmercaptoanilino)pyrrolidine.

Preparation 1 8.--l-methyl-3- (4-dimethylaminoanilino) pyrrolidine Usingthe method of Preparation 13, (1-methyl-3-pyrrolidyl)-benzenesulfonateis prepared and reacted with 4-dimethylaminoaniline to produce1-methyl-3-(4-dimethylaminoanilino) pyrrolidine.

In the same manner, numerous other 1-substituted-3- anilinopyrrolidineswithin the scope of Formula IV are prepared.

Where the foregoing preparations produce a compound haying a methyl orother lower-alkyl group, it is to be understood that compoundscontaining other lower-alkyl groups of straight or branched nature andcontaining up to eight carbon atoms inclusive, such as methyl, ethyl,propyl, isopropyl, butyl, sec. butyl, t. butyl, amyl, isoamyl, hexyl,heptyl, and octyl, are prepared in the same manner by substitution inthe process of the appropriate difierent lower-alkyl starting material.Likewise, where chloro or other halogen atom is present, althoughchlorine is preferred, further halogen compounds including iodo, bromo,chloro, and fluoro compounds are prepared starting from the appropriatehalogenated starting material. Similarly, where methoxy or otherlower-alkoxy group is present, other lower-alkoxy groups containingvarious lower alkyl groups having up to eight carbon atoms inclusive areprepared in the same manner from the appropriate different lower-alkoxystarting material. Moreover, when one dilower-alkylamino group, such asthe dimethylamino group, is present in a compound, otherdilo'wer-alkylamino compounds are prepared in the same manner startingonly with the selected different diloweralkylamino compound. -In thesame manner, ortho and meta substituted compounds are produced insteadof the para by utilizing the selected ortho or meta substituted startingcompound, and vice versa. Similarly, other molecular changes are readilymade.

As shown in Chart 1, the general procedure for the preparation of thecompounds of the invention involves either one or several steps,depending on whether a 4-beta-haloethyl derivative (VI) or another4-beta-substituted ethyl derivative (VII) is desired, since in thelatter case a subsequent replacement of the chlorine atom is alsorequired. In either case, the appropriately substituted3-aminopyrrolidine (IV) is first used as starting material, and isallowed to react with a carbonyl halide, as for example, phosgene orcarbonyl bromide, which results in production of the resultingintermediate carbamylhalide (V), with spontaneous or nearly spontaneousrearrangement and cleavage of the pyrrolidine ring and formation of animidazolidinone ring. Heating does facilitate the reaction but 1s notalways essential.

A suitable general procedure for carrying out the process of theinvention is as follows:

A solution of phosgene, or other carbonyl halide, such as carbonylbromide, is placed in a suitable reaction vessel, e.-g., a three-neckround-bottomed flask equipped with a stirrer, reflux condenser,thermometer and dropping funnel, employing a solvent which is inertunder the reaction conditions. Suitable solvents are chloroform,methylene chloride, and the like. The reaction may be carried out at anysuitable temperature and in any suitable manner. A preferred temperaturerange is about zero to 25 C. About five hundred milliliters of solventper mole of phosgene provides a suitable solution. The appropriate1-al-kyl-3-arylaminopyrrolidine (IV) is added dropwise with stirringwhile maintaining the temperature within the desired range. Thesubstituted-pyrrolidine reactant is used in a quantity which preferablyis at least equimolar to the phosgene or other carbonyl halide used.However, it is preferred that an excess of phosgene, as for exampleabout two molar equivalents, be used in order to improve the yield ofthe desired product. The temperature may be allowed to rise slowly toroom temperature over a suitable period as, for example, about one totwo hours, and the solution finally permitted to reflux for a suitableperiod, such as about four to forty eight hours. Although the reactionmay be carried out at room temperature, elevated temperatures may beadvantageously used to shorten the reaction time. After a suitablereaction period, the reaction mixture is cooled to a suitabletemperature as for example about zero to 10 C. and the product isseparated and isolated in an appropriate manner. The isolation stepusually comprises washing the reaction mixture with aqueous mineralacid, aqueous alkali, drying, and concentrating and crystallizing theresidue from an appropriate solvent. To facilitate purification when aproduct is not crystalline, the residue may be distilled at reducedpressure. The resulting product is the4beta-haloethyl-1,3-disubstituted-Z-imidazolidinone (VI).

Conversion of the halo-derivative (VI), prepared as in the steppreviously described, to a 4-beta-aminoethyl-1, 3disubstituted-2-imidaz0lidinone (VII) may be carried out by allowing thehalo-derivative (VI) to react with an amine, such as morpholine,dimethylamine, or diet-hylamine. Any suitable reaction procedure may beused. An excess of the amine is frequently employed.

In the case of relatively non-volatile amines such as morpholine, thehalo-derivative is refluxed, usually with at least two molar equivalentsof amine, until the reaction is substantially complete. The exactreaction time required may vary depending upon the particular amineused, but two hours is generally sufiicient for complete reaction. Asolvent, e.g., ethanol, isopropanol, dioxane, ethylene glycol, or thelike, may be used, but such solvent is not essential. The excess amineand solvent are removed on a steam bath under reduced pressure. Theresidue is isolated and the product purified in any appro riateconventional manner.

Reaction of the halo-derivative (VI) with an excess of a volatile amine,such as dimethylamine, may be conducted in a stainless steel reactionbomb employing a suitable reaction solvent, e.g., ethanol, isopropanol,dioxane, or the like. The reactants together with the solvent are sealedin the bomb and heated to a suitable temperature, as for example, about75-200" C. The reaction may occur at room temperature, but elevatedtemperatures are usually advantageously employed to shorten the reactionperiod. The length of the reaction time varies with the type of amineand the temperature range employed, two hours of heating at temperatureswithin the range of 150 C. usually being sufiicient to complete thereaction. A longer heating period may frequently be used without anyresultant harm to the product. The bomb is 11 cooled and any excessamine and solvent are removed, as under reduced pressure on asteam-heated rotary evaporator. The residue may then be isolated andpurified in the manner as described above.

Procedure for the conversion of the halo-derivative (VI) to derivatives(VII) other than amines, such as hydroxy, acyloxy, methoxy, phenoxy,mercapto, and the like, is given immediately preceding the examplesillustrating the same.

The following examples are given by way of illustration only and are notto 'be construed as limiting.

The examples immediately following illustrate the preparation of1,3-disubstituted-4-(Z-haloethyl)-2imidazolidinones according to theinvention.

Example 1.-4-(2-chloroethyl)-1-methyl-3-phenyl-2- imidazolidinone Asolution of phosgene (0.88 mole) in chloroform (500 ml.) was placed in atwo-liter three-necked roundbottomed flask fitted with a stirrer,condenser, dropping funnel and thermometer, and cooled to zero C. Whilstirring and maintaining the temperature at 10-15 C.,1-methy1-3-anilino-pyrrolidine (0.44 mole) was added dropwise. Oncompleting the addition of the substituted pyrrolidine, stirring wascontinued for two hours while the temperature rose to 25-30 C. Thetemperature of the reaction mixture was then raised to reflux for aperiod of twelve hours. The reaction mixture was cooled to -5 12 C., andwashed with hydrochloric acid (6 N, 200 ml.). The chloroform layer wasallowed to separate and then washed several times with water. Thechloroform extracts were dried over anhydrous sodium sulfate, filtered,and the chloroform evaporated on a rotary steam evaporator undermoderate reduced pressure. The isolated residue was purified by vacuumdistillation under reduced pressure. The Z-imidazolidinone derivativeexhibited a boiling range of 186-190 C. at 0.1 mm. Hg pressure (re- 10crystallized from isopropyl ether; melting point 51-52 C.) and wasobtained in 86% yield based on the starting pyrrolidine.

Analysis.Calculated for C H ClN O: C, 60.37; H, 6.33; N, 11.74; Cl,14.85. Found: C, 60.40; H, 6.44;

15 N, 11.71; Cl, 14.76.

Example 1A.-4- (2-bromoethyl) -1-methyl-3-phenyl-2- imidazolidinoneUtilizing the method of Example 1, l-methyl-3-anilinopyrrolidine isreacted with a solution of carbonyl bromide (COBr in chloroform to give4-(2-bromoethyl)-1-methyl-3-phenyl-2-imidazolidinone.

listed in Table IH.

TABLE IH.-EXAMPLES 2 THROUGH 11 Example 2-Imidazolidinone P., PressureM.P., Yield, Number 0. (mm. Hg) 0. percent Remarks o p R-group 2 C2115CH 195-200 0.08 67-68 3 CzHs HzCQ- 172-176 0. 04 70 m; 1.5447; paleyellow oil.

4 01H; 01- 176-180 0. 05 00 Yellow oil.

5 0 H; ornoQ- 205-207 0. 05 87 Clear amber 011.

l 6 02H; 152-157 0. 06 73 Pale yellow viscous oil; m) 1.5181. 1 011mmour. 107-170 0. 02 07-00 43 8 CH(GH3)2 Q 168-170 0.05 41 Pale yellowoil; n0 1.5424.

Cl CH:

I l 0 omoHm Q- -107 0005 45 10. C HgCHz CeHs 228-232 0. 2 41 11 02H:-188 0. 03 25 Pale yellow viscous oil.

TABLE III.EXAMPLES 2 THROUGH 11Contiuued Analytical Data on Examples 2through 11 Calculated Found Example Number Empirical Formula C H N 01 CH N 01 CnHnClNzO 61. 77 6.78 11.08 14. 03 61. 93 6. 76 11. 01 13. 95

CISHfllCl-NZO 64. 16 7. 54 9. 98 64.43 7. 52 9. 77 CnHmCIzNzO 54. 36 5.62 9. 76 24. 69 54. 52 5. 42 9. 47 24. 37 CHHlQClNZOfi 59. 46 6. 77 9.9112. 54 59. 51 6.71 9. 69 12. 61

CHHlflClFJNZ O 52. 42 5. 03 8. 73 52. 42 5.01 8. 62 C H1pC1N2O 63. 03 7.18 10. 50 13. 29 63. 07 7. 08 10. 66 12. 92 CflHzzClNzO 64. 16 7. 54 9.98 64. 75 7. 67 10.07 CH20Cl2N2O 57. 14 6. 4O 8. 89 22. 50 57. 33 6. 278. 67 22. 39 C1gH C1NgO 68. 67 6. 08 8. 90 11.26 68. 70 6.03 9.16 11. 1011 C 17H GIN 20 67. 42 6. 32 9. 11. 71 68. 10 6. 33 9. 46 11. 11

Utilizing the process of Example 1 above, the following compounds areprepared from the stated starting materials:

4 (2 chloroethyl) 1 cyclohexyl 3 phenyl 2- imidazolidinone by reacting 1cyclohexyl 3 anilinopyrrolidine and phosgene.

4 (2 chloroethyl) 1 cyclohexenyl 3 phenyl- 2 imidazolidinone by reacting1 cyclohexenyl 3- arrilinopyrrolidine and phosgene.

4 (2 chloroethyl) 1 allyl 3 phenyl 2 imidazolidinone by reacting 1 allyl3 anilinopyrrolidine and phosgene.

4 (2 chloroethyl) 1 methyl 3 (2 methylmercaptophenyl) 2 imidazolidinoneby reacting 1- methyl 3 (2 methylmercaptoanilino)pyrrolidine withphosgene. v

4 (2 chloroethyl) 1 allyl 3 phenyl- 2 imidazolidinone by reacting 1allyl 3 anilinopyrrolidine 3 (4 dimethyl aminoanilino)pyrrolidine withphosgene.

As indicated in the foregoing, the 4 (2 haloethyl)- Z-imidazolidinonesare convertible into numerous other corresponding 4 (3 substitutedethyl) 2 imidazolidinones. The various beta substitutents are generallyintroduced into the 4-ethyl group of the 2-imidazolidinone bydisplacement of the beta halogen with an appropriate basic residue.These reactions are generally carried out by heating an alkali metal,e.g., sodium, salt of an alcohol, phenol, inorganic acid, or organicacid with the 1,3 disubstituted 4 (2 haloethyl) 2 imidazolidinone in anappropriate solvent followed by a conventional isolation of the product.

The 4 (2 alkanoyloxyethyl) 2 imidazolidinone compounds are prepared fromthe selected 4 (2 haloethyl) 2 imidazolidinone by the conventionaldisplacement route, as with an appropriate alkali metal salt of theselected acid, e.g., a sodium alkanoate such as sodium acetate or thelike, preferably in dimethylformamide solvent, according to standardprocedure, as indicated by the following examples.

Example 12.4 (2-acetoxyethyl)-1-methyl-3-phenyl-2- imidazolidinone Asolution of 4 (2 chloroethyl) 1 methyl 3 phenyl 2 imidazolidinone (0.2mole) and sodium acetate (0.22 mole) in dimethylformamide (500milliliters) was stirred at reflux for fifteen hours. Thedimethylformamide was then removed under reduced pressure and theremaining concentrate partitioned between chloroform and water. Thechloroform extracts were washed with water and dried over sodiumsulfate. Evaporation of the chloroform yielded white crystals which wererecrystallized from isopropyl ether. The product was obtained in 80%yield and had a melting range of 82-83 C.

Analysis.Calculated for C H N O C, 64.10; H, 6.92; N, 10.68. Found: C,63.85; H, 6.86; N, 10.59.

Example 13.4 (2 acetoxyethyl) 1 ethyl 3 phenyl-Z-imidazolidinone The 2imidazolidinone derivative was prepared according to the proceduredescribed in Example 12 except that 4 (2 chloroethyl) 1 ethyl 3 phenyl2- imidazolidinone was employed instead of 4 (2 chloroethyl) 1 methyl 3phenyl 2 imidazolidinone. The product was isolated in 91% yield and hada boiling range of 185190 C. at 0.005 mm. Hg pressure.

Analysis.-Calculated for C H N O C, 65.19; H, 7.30; N, 10.14. Found: C,65.30; H, 7.38; N. 9.94.

Example 14.-4 (2 acetoxyethyl) 1 ethyl 3 (3- trifluoromethylphenyl)-2-imidazolidinone The acetoxy derivative was prepared according to theprocedure described in Example 12 except that 4-(2- chloroethyl) 1 ethyl3 (S-trifluoromethylphenyl) -2- imidazolidinone was employed as theZ-imidazolidinone reactant. The product was removed by distillationunder reduced pressure; boiling point 164l66 C. at 0.03 mm. Hg pressure;96% yield.

Analysis.-Calculated for C H F N O C, 55.81;H, 5.56; N, 8.14. Found: C,55.53; H, 5.75; N, 8.18.

The 4-beta-hydroxyethyl compounds may be prepared by direct hydrolysisof the corresponding beta-haloethyl compound according to conventionalbasic hydrolysis procedure, but yields are less than optimum and it istherefore preferred to convert the haloethyl compound to an acyloxy,e.g., lower-alkenoyloxy such as acetoxy, compound and thereafterhydrolyze according to conventional basic hydrolysis procedure to thehydroxy group, which has the advantage of excellent yields.

The 4 (beta hydroxyethyl) derivatives were, for example, prepared byhydrolyzing the acetates with aqueous sodium hydroxide as per thefollowing examples.

Example 15.-4 (2 hydroxyethyl) 1 methyl 3- phenyl 2 imidazolidinone Anethanolic solution of sodium hydroxide (0.13 mole in 100 milliliters 95%ethanol) was added to 4 (2- acetoxyethyl) 1 methyl 3 phenyl 2imidazolidinone (0.1 mole) and the mixture gently refluxed for threehours. The reaction mixture was then evaporated to a small volume. Theproduct crystallized on cooling. The product was recrystallized fromisopropanol, melting point 98.5-99 C.; 93% yield.

Analysis.Calculated for C H N O C, 65.43; H, 7.32; N, 12.72. Found: C,64.93; H, 7.30; N, 12.77.

Example 16.4 (2 hydroxyethyl) 1 ethyl-3-phenyl- Z-imidazolidinone ThisZ-imidazolidinone derivative was prepared according to the methoddescribed in Example 15 except that 4 (2 acetoxyethyl) 1 ethyl 3 phenyl2 imidazolidinone was employed as the substituted 2 imidazolidinonereactant. The product was isolated in 96% yield and recrystallized fromisopropanol, melting point 99-100 C.

Analysis.-Calculated for C H N O C, 66.64; H, 7.74; N, 11.96. Found: C,66.59; H, 7.56; N, 11.75.

The 4 (2 ether substituted) 2 imidazolidinones,

e.g., the lower-alkoxy compounds, are prepared from the corresponding4-haloethyl compounds by conventional replacement of the halogen atomusing an alkali metal alcoholate or an alkali metal, e.g., sodium,solution of the selected alcohol, the alcohol or alcohol moiety ineither case corresponding to the group desired to appear in the betaposition of the 4-ethyl group. Some representative ether formations areillustrated in the example below.

Example 17.4-(2-methoxyethyl)-1-isopropyl-3-phenyl- Z-imidazolidinone Asolution of 0.1 mole of4-(2-chloroethyl)-1-isopropyl-3-phenyl-imidazolidinone in 150milliliters of absolute methanol is added to fifty milliliters ofabsolute methanol in which 2.5 grams (0.11 gram atoms) of sodium havebeen dissolved. The solution is heated in a closed system for sixteenhours at 140 C. Fifty milliliters of water is added to the resultingmixture and the product which separates is recrystallized from amethanol-water mixture, to give4-(2-methoxyethyl)-l-isopropyl-3-phenyl-2-imidazolidinone.

Example l8.4-(2-mercaptoethyl) l-ethyl-3-phenyl- 2-imidazolidinone Asolution of sodium hydrogen sulfide dihydrate and 4(2-chloroethyl)-l-ethyl-3-phenyl-2-imidazolidinone in 85% ethanol arerefluxed together for a period of several hours and subsequentlyconcentrated in vacuo. The residue is partitioned between chloroform andwater and the chloroform layer dried over anhydrous sodium sulfate andconcentrated in vacuo. The distillate is then crystallized from anethanol-Water mixture to give 4(2-mercaptoethyl) -1-ethyl-3-phenyl-2-imidazolidinone.

Example 19.4-(Z-methylmercaptoethyl)-1-ethyl-3-phenyl-Z-imidazolidinone.

A solution of methyl bromide in absolute ethanol is added to a solutionof 4-(2-mercaptoethyl)-l-ethyl-3- phenyl-Z-imidazolidinone in 200milliliters of absolute ethanol containing 1.5 grams of sodium. Thesolution is stirred at room temperature for about four hours andconcentrated in vacuo and the residue partitioned between water andchloroform. The chloroform is concentrated in vacuo and the residuecrystallized from 70% ethanol, to give 4-(2 methylmercaptoethyl)-l-ethyl3-phenyl-2-imidazolidinone.

The 4-(beta-cyanoethyl)-2-imidazolidinones are prepared in conventionalmanner by reaction of the selected 4-haloethyl-2-imidazolidinone with analkali metal cyanide, e.g., sodium cyanide, usually by heating thereactants together in a suitable organic solvent, preferablydimethylformamide or the like, to introduce the cyano group in place ofthe halogen atom, and thus to extend the 4-ethyl carbon chain. Arepresentative example of this procedure follows.

Example 20.1-isopropyl-3-phenyl-2-imidazolidinone- 4-propionitrile Amixture of 1.0 mole of 4-(2-chloroethyl)-1-isopropyl-3-phenyl-2-imidazolidinone and 75 grams (1.5 moles) of sodium cyanide inone liter of dimethylformamide is stirred and heated to a temperature of100 C., over a one-hour period, and this temperature maintained for anadditional three hours. The mixture is poured into ice water and theprecipitated solid filtered and recrystallized from isopropanol.

Other compounds prepared in the same manner include 1methyl-3-phenyl-2-imidazolidinone-4-propionitrile and1-ethyl-3-phenyl-2-imidazolidinone-4-propionitrile.

Using the process described in Example 20, the following compounds areprepared from the stated starting materials:

1 :benzyl-3 phenyl-Z-imidazolidinone-4-propionitrile by reacting 4(2-chloroethyl)-1-be11Zyl-3-phenyl-2-imidazolidinone and sodium cyanide,

1 cyclohexyl 3-phenyl-2-imidazolidinone-4-propionitrile by reacting4-(2-chl0roethyl)-1-cyclohexyl3-pheny1- Z-imidazolidinone and sodiumcyanide.

1 cyclohexeny1-3-phenyl-Z-imidazolidinone-4-propionitrile by reacting4-(2-chloroethyl)-1-cyclohexenyl-3-phenyl-2-imidazolidinone and sodiumcyanide.

1-allyl-3-phenyl-2-imidazolidinone-4-propionitrile by reacting 4 (2chloroethyl)-1-allyl-3-phenyl-2-imidazolidinone and sodium cyanide.

1-methyl-3-(4-methylphenyl) 2 imidazolidinone 4- propionitrile byreacting 4-(2-chloroethyl)-l-methyl-3- (4-methylphenyl)-2-imidazolidinone and sodium cyanide.

1 methyl-3-(2,4-dimethylphenyl)-2-imidazolidinone-4- propionitrile byreacting 4-(2-chloroethyl)-1-methyl-3-(2,4-dimethylphenyl)-2-imidazolidinone and sodium cyanide.

1 methyl 3-(4-methoxyphenyl)-2-imidazolidinone-4- propionitrile byreacting 4-(2-chloroethyl)-1-methyl-3-(4-methoxyphenyl)-2-imidazolidinone and sodium cyanide.

1 methyl-3-(4-chlorophenyl)-2-imidazolidinone-4-propionitrile byreacting 4-(2-chloroethyl)-1-methyl-3- (4-chlorophenyl)-2-imidazolidinone and sodium cyanide.

l-methyl-3-(3-trifiuoromethylphenyl) 2 imidazolidinone-4-propionitrileby reacting 4-(2-chloroethyl)-lmethyl 3-(3trifluoromethylphenyl)-2-imidazolidinone and sodium cyanide.

1 methyl 3-(3-chloro-2-methylphenyl)-2 imidazolidinone-4-propionitrileby reacting 4-(2-chloroethyl)-1- methyl 3-(3chloro-Z-methylphenyl)-2-imidazolidinone and sodium cyanide.

1 methyl-3- (4 methylmercaptophenyl) -2-imidazolidinone-4-propionitrileby reacting 4-(2-chl0roethyl)-'1- methyl-3-(4 methylmercaptophenyl)Z-imidazolidinone and sodium cyanide.

1 methyl-3-(4 d-imethylaminophenyl) -2-imidazolidinone-4-propionitrileby reacting 4-(2-chloroethyl)-1- methyl-3-(4 dimethylaminophenyl)Z-imidazolidinone and sodium cyanide.

The 4-(2-carboxyethyl)-2-imidazolidinones are prepared by conventionalacid hydrolysis of the corresponding 4-(2cyanoethyl)-2-imidazolidinones,employing a concentrated mineral acid reagent. A reaction period oftwenty-four hours and a temperature not in excess of 100 C. is usuallyadequate. The following example indicates the hydrolysis procedureemployed.

Example 21 .1-isopropyl-3-phenyl-2-imidazoldinone- 4-propionic acid Amixture of 0.28 mole of l-isopr0py1-3 -phenyl-2-imidazolidinone-4-propionitrile and 500 milliliters of 70% sulfuric acidis stirred and heated at -90 C. for twenty-four hours and poured intoice and water. The precipitated solid is filtered and recrystallizedfrom a chloroform-ligroin mixture.

The 4-(beta-caIb-lower-alkoxy ethyl) 2 imidazolidinones are preparedfrom the 4-(beta-carb0xyethyl)-2- imidazolidinones by standardesterification procedure involving the acid and the selected alcohol inthe presence of a suitable esterification catalyst, e.g., hydrogenchloride, sulfuric acid, cation exchange resins, or an aromatic sulfonicacid such as benzene or p-toluene sulfonic acid, preferably with removalof either the ester product or Water of reaction if optimum yields aredesired. Alternatively, the acid may be reacted with a diazoalkane,e.g., diazomethane, in excellent yield, or an alkyl halide may bereacted With an alkali metal salt of the acid, in usual manner.Alternatively, the acid may first be converted to an acid halide as bytreatment with thionyl chloride or bromide, phosphorus trichloride ortribromide, or the like, in the accepted manner for such type reactions,and the acid chloride then reacted with a selected alkanol or phenol oralkali metal salt thereof to give high yields of the desired ester. Thefollowing example is representative of the preparation of an acid halideof a 4-(2-carboxy- 1 7 ethyl)-2-imidazolidinone, and the subsequentexample is indicative of the esterification of a 4-(2-carboxyethyl)-2-imidazolidinone to produce a lower-alkyl ester of a 4-(2-carboxyethyl)-2-imidazolidinone.

Example 22.1-isopropyl-3-phenyl2-imidazolidinone- 4-propionyl chloride Asuspension of 0.41 mole of l-isopropyl-3-phenyl-2-imidazolidinone-4-propionic acid in 500 milliliters of dry benzene istreated at 20-25 C. dropwise with stirring with 97.5 grams (0.82 mole)of thionyl chloride. The resulting solution is refluxed for one hour andconcentrated in vacuo. The residue is crystallized from benzene.

Example 23.-Ethyl-l-isopropyl-3-phenyl-2-imidazolidinone-4-propionate To200 milliliters of dry ethanol is added 2.05 grams (0.09 mole) ofsodium. When solution is complete, 0.08 mole of1-isopropyl-3-phenyl-2-imidazolidinone-4-propionyl chloride in 300milliliters of dry ethanol is added rapidly. The mixture is stirred atroom temperature overnight and filtered. The filtrate is concentratedand the residue partitioned between 250 milliliters of chloroform and250 milliliters of water. The chloroform solution is dried overanhydrous sodium sulfate and concentrated. The residue is crystallizedfrom 70% ethanol.

The 4-(beta-carbamylethyl)2-imidazolidinones are prepared by reaction ofammonia or an amine with a 4-(2- carbalkoxycthyl)-2-imidazolidinone orthe acid halide of a 4-(2-carboxyethyl)-2-imidazolidinone, preferablythe latter. The reaction is usually conducted using cold concentratedammonium hydroxide to produce the primary amide, or using a primary orsecondary amine in a hydrocarbon, e.g., benzene, solvent at atemperature between room temperature and the reflux temperature of thesolvent involved, usually 2080 C., to produce the primary or secondaryamine-containing carbamyl radicals, such as N-phenylorN-(loweralkyl)-carbamyl and N,N-di(loweralkyD-carbamyl, as well asN,N-diphenylloWer-alkyl, e.g., N,N-dibenzyl and carbamyl N,N-monocyclicalkyl or N-saturated heterocyclic-carbamyl radicals, wherein thesaturated monocyclic heterocyclic radical is as set forth hereinbeforeunder the definition of amino. Representative of the preparation ofvarious types of 4-(betacarbamylethyl)-2-imidazolidinones are the threeexamples which immediately follow.

Example 24.1-isopropyl-3-phenyl-2-imidazolidinone-4-propionamide 1isopropyl 3 phenyl 2 imidazolidinone 4 propionyl chloride (0.146 mole)is added in small portions to cold, concentrated ammonium hydroxidesolution. The mixture is stirred vigorously during the addition and foran additional half hour and the resulting solid filtered, washed withwater and crystallized from a chloroformligroin mixture.

Example 25.-1-isopropyl-3-phenyl-2-imidazolidinone- 4-(N-methylpropionamide) A solution of 7.75 grams (0.25 mole) ofmethylamine in 150 milliliters of benzene is added dropwise withstirring to a suspension of 0.068 mole of 3-phenyl-1-isopropyl-2-imidazolidinone-4-propionyl chloride in benzene. After addition,the preparation is brought slowly to reflux and reflux continued for onehour. The solvent is evaporated and the residue crystallized frommethanol.

Example 26.1isopr0pyl-3-phenyl-2-imidazolidinone- 4-(N,N-dimethylpropionamide) 1 isopropyl 3 phenyl 2 imidazolidinone 4-(N,N-dimethylpropionamicle) is prepared in the manner of the precedingexample from l-isopropyl-3-phenyl-2- imidazolidinone-4-propionylchloride and dimethylamine.

In the same manner, other N,N-diloweralkyl and the correspondingN,N-dicyclopentyl and N,N-dicyclohexyl compounds, as well as thecorresponding piperazinocarbonyl, piperidinocarbonyl,pyrrolidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl,dilower-alkylpiperazinocarbonyl, and like compounds are also prepared.

The 4-(2-aminoethyl)-2-imidazolidinone compounds are generally preparedby heating a solution of the selected 4-(2-haloethyl)-2-imidazolidinoneand the selected amine in a suitable reaction solvent, e.g., ethanol, ahigher boiling alcohol such as butanol, a hydrocarbon solvent such astoluene, or the amine itself may be the solvent in some cases. Areaction temperature from about room temperature to about 120 C. isemployed, preferably 100 to 120 C., and a reaction period of about eightto twenty-four hours is usually adequate. Higher reaction temperaturesincrease the speed of reaction but tend to increase the incidence ofundesired side reactions, while temperatures below 100 C. frequentlyrequire undesirably lengthy reaction periods. Pressure to the extentgenerated in a sealed system is frequently employed to facilitate thereaction. The amine is usually employed in excess, at least two molarequivalents of the amine being preferred per each molar equivalent ofstarting halogen compound. The resulting solution of the amine reactionproduct is concentrated, as in vacuo, and the amine product isolated,usually as a crystalline hydrohalide salt. In most cases the hydrohalidesalts, e.g., the hydrochloride, crystallize as the hydrate. In caseswhere a crystalline salt is difiicult or impossible to obtain, the freebasic amine itself may be distilled and crystallized from a solvent orsolvent mixture or alternatively isolated as an oil by fractionaldistillation. Extraction of the reaction product with a suitablesolvent, e.g., ether, benzene, toluene, or ethyl acetate, frequentlyassists in recovering all of the available prodnet for isolation bycrystallization or the like and concentrated acid, e.g., 2 N HCl, oranhydrous ketones, e.g., methyl ethyl ketone, are frequently of value asthe solvent or medium from which crystallization or recrystallization iseflected. Where the free base is desired, this may be obtainedconventionally by neutralizing the reaction product or a solution of theisolated salt with a base such as ammonia, ammonium hydroxide, sodiumcarbonate, or other suitable alkaline material, extracting the liberatedbase with a suitable solvent such as ethyl acetate or benzene, dryingthe extract and evaporating to dryness in vacuo or fractionallydistilling, or in other conventional manner. Numerous acid addition aswell as quaternary ammonium (onium) salts may be prepared from the freebases, either isolated or without isolation from the reaction product,as already indicated in the foregoing. The amine preparation isillustrated by the following specific examples.

Example 27.-4- 2-pyrrolidinoethyl) -l-ethyl-3- 3-trifluoromethylphenyl)-2-imidazolidine fumarate An excess of pyrrolidine (200 milliliters) wasadded to 4-(2-chloroethyl) 1 ethyl-3-(3-trifluoromethylphenyl)-Z-imidazolidinone (0.078 mole) and the mixture was refiuxed for twelvehours. Excess pyrrolidine was removed under reduced pressure and theconcentrate partitioned between ether and water. The ether extracts werewashed with water, dried over sodium sulfate and the ether removed byevaporation. The residual oil (free base; yield) was dissolved inisopropanol and treated with fumaric acid. The product crystallized onaddition of a. small amount of isopropyl ether. The resultant fumaratesalt was recrystallized from methyl ethyl ketone and ether, meltingpoint -160.5 C.

Analysis.Calculated for C22H28F3N305: C, H, 5.99; N, 8.91. Found: C,56.18; H, 6.10; N, 8.86.

Example28.4-(2-rnorpholinoethyl)-1-ethyl-3-(trifiuoromethylphenyl)-2-imidazolidinonefumarate This compound was prepared in the manner of the precedingexample except that morpholine was used instead of pyrrolidine. Themorpholine hydrochloride was iso- Example 29.4-(2-morpholinoethyl)-1-isopropyl-3- phenyl-2-imidazolidinone Morpholine (100 milliliters)was added to 4-(2-chloroethyl)-1-isopropyl-3-phenyl 2 imidazolidinone(0.585 mole) and the solution refluxed for two hours. Excess morpholinewas removed on a steam bath under reduced pressure and the residue thendissolved in dilute aqueous hydrochloric acid (200 milliliters). Thesolution was washed with ether. The aqueous acid solution was made basicwith sodium hydroxide and extracted with chloroform. The chloroformextract was dried over sodium sulfate and concentrated. The residuecrystallized on standing; 94.5% yield. The product was recrystallizedfrom isopropyl ether, melting point 88 C.

Analysis.Calculated for C13H27N3O2Z C, 68.11; H, 8.58; N, 13.24. Found:C, 68.17; H, 8.49; N, 13.17.

Example 3 0.4-(2-morpholinoethyl) -1-cyclohexyl-3-phenyl-Z-imidazolidinone maleate An excess of morpholine (200milliliters) was added to 4 (2 chloroethyl) 1 cyclohexyl 3 phenyl 2-imidazolidinone (0.16 mole) and the solution was refluxed for 48 hours.On cooling, the morpholine hydrochloride crystallized out and wasremoved by filtration. The remaining filtrate was concentrated on arotary steam evaporator at reduced pressure. The concentrate was madeacid with aqueous hydrochloric acid (6 N) and extracted with ether. Theacid solution was then made basic with aqeous sodium hydroxide (6 N) andextracted with ether. The ether extract from the basic aqueous solutionwas dried and evaporated to yield an oil which was converted to themaleate salt from an isopropanol and isopropyl ether solvent system. Theproduct melted at 141-142 C. and was obtained in 90% yield.

Analysis-Calculated for CH35N306: C, H, 7.45; N, 8.87. Found: C, 63.64;H, 7.45; N, 8.93.

Example 3 l.4-(2-morpholinoethyl) -1-benZyl-3-phenyl- 2-imidazolidinoneAn excess of morpholine (50 milliliters) was added to 4 (2 chloroethyl)1 benzyl 3 phenyl 2 imidazolidinone (0.0635 mole) and the reactionsolution was refluxed for four hours. The reaction solution was thencooled and concentrated in vacuo. The residue was dissolved in diluteaqueous hydrochloric acid and washed with isopropyl ether to remove anyunreacted material. The aqueous acid layer was extracted with chloroformand the chloroform extract containing the hydrochloride was washed withdilute aqueous sodium hydroxide to form the free base, dried over sodiumsulfate and concentrated in vacuo. The product was recrystallized from50% ethanol, melting point 1l912l C.; 39% yield.

Analysis.Calculated for C22H27N3O2Z C, 72.30; H, 7.45, N, 11.50. Found:C, 72.18; H, 7.58; N, 11.31.

Example 32.4-( Z-dimethylaminoethyl) -1-ethyl-3-(4methoxyphenyl)-2-imidazolidinone hydrochloride A stainless steel bombwas charged with 4-(2-chloroethyl) 1 ethyl 3 (4 methoxyphenyl 2imidazolidinone (0.1 mole), absolute ethanol (100 milliliters) anddimethylamine (3.0 moles). The bomb was sealed and heated for 24 hoursat 150 C. The reaction mixture was chilled and transferred to a flaskwhere excess amine and ethanol were removed under reduced pressure. Theresidue was acidified, washed with ether, then basified with sodiumhydroxide (6 N aqueous solution) and extracted with ether. The etherextracts were dried, the ether removed under reduced pressure and theresidue (free base) vacuum distilled; boiling point 172-177 C. at 0.008mm. Hg. pressure. The free base was converted to the hydrochloride saltby treatment of an isopropanol solution of the base with an etherealsolution of hydrochloric acid. The hydrochloride salt was recrystallizedfrom isopropanol-isopropyl ether solvent in 30% yield, melting point,153153.5 C.

Analysis.Calculated for C H ClN O C, 58.61; H, 7.99; N, 12.82; Cl,10.82. Found: C, 58.83; H, 8.15; N, 12.58; Cl, 10.73.

Example 33 .4-(2-dimethylaminoethyl)1-ethyl-3- phenyl-2-imidazolidinonehydrochloride Utilizing the method of Example 31, 4-(2-chloroethyl)-l-ethyl-3-phenyl 2 imidazolidinone is reacted with dimethylamine to give4-(2-dimethylaminoethyl)-l-ethyl- 3-phenyl-2-imidazolidinone.

Example 34.-4-(2-diethylaminoethyl)-1-ethyl-3-(4-methoxypheny1)-2-imidazolidinone fumarate The same procedure wasemployed as described in the preceding example except that diethylaminewas used instead of dimethylamine. The free base was isolated bydistillation under reduced pressure; boiling point 173- C. at 0.0075 mm.Hg pressure. The free base was converted to the fumarate salt inisopropanol and crystallized on dilution with a small quantity ofisopropyl ether in 28% yield, melting point l33134 C.

Analysis.Calcul-ated for C H N O 1 C, 60.67; H, 7.64; N, 9.65. Found: C,60.78; H, 7.77; N, 9.44.

Using the process described in Example 32, the following compounds areprepared from th stated starting materials:

4 (2 morpholinoethyl) 1 cyclohexyl-3-phenyl-2- imidazolidinone byreacting 4-(2-chloroethyl)-1-cyclohexyl-3-phenyl-2-imidazolidinone withmorpholine.

4 (2 morpholinoethy-l)-1-allyl-3-phenyl-2-imidazolidinone by reacting4-(2-chloroethyl)-1-allyl-3-phenyl2- imidazolidinone with morpholine.

4 (2 dimethylaminoethyl) 1 ethyl-3-(4-methylphenyl)-2-imidazolidinone byreacting 4-(2-ch1oroethyl)- 1-ethyl-3-(4-methylphenyl) 2 imidazolidinonewith dimethylamine.

4 (2morpholinothyl)-l-isopropyl-S-(2-,4-dimethylphenyl)-2-imidazolidinone byreacting 4-(2-chloroethyl)- 1-isopropyl-3-(2,4-dimethylphenyl) 2imidazolidinone with morpholine.

4 (2 morpholinoethyl) 1 isopropyl-3-(2-chlorophenyl)-2- imidazolidinoneby reacting 4-(2-chloroethyl)- 1-isoproply-3-(2chlorophenyl)-2-imidazolidinone with morpholine.

4 (2 morpholinoethyl)-1-isopropyl-3-(4 chloro-2-methylphenyl)-2-imidazolidinone by reacting 4-(2-chloroethyl) 1isopropyl 3 (4-chloro-2-methylphenyl)-2- imidazolidinone withmorpholine.

4 (2diethylaminoethyl)-1-ethyl-3-(4-methylmercaptophenyl)-2-imidazolidinoneby reacting 4-(2-chloroethyl) 1ethyl-3-(4-methylmercaptophenyl)-2-imidazolidinone with diethylamine.

4 (2 diethylaminoethyl) 1ethyl-3-(4-dimethylaminophenyl)-2-irnidazolidinone by reacting4-(2-chloroethyl) l ethyl-3-(4-dimethylaminophenyl)-2-imidazolidinonewith diethylamine.

Where the foregoing examples produce a compound having a methyl or otherlower-alkyl group, it is to be understood that compounds containingother lower-alkyl groups of straight or branched nature and containingup to eight carbon atoms inclusive, such as methyl, ethyl, propyl,isopropyl, butyl, sec. butyl, t. :butyl, amyl, isoamyl, hexyl, heptyl,and octyl, are prepared in the same manner by substitution in theprocess of the appropriate different lower-alkyl starting material.Likewise, where chloro or other halogen atom is present, althoughchlorine is preferred, further halogen compounds including iodo, bromo,chloro, and fluoro compounds, are prepared starting from the appropriatehalogenated starting material. Similarly, where methoxy or otherlower-alkoxy group is present, other lower-alkoxy groups containingvarious lower-alkyl groups having up to eight carbon atoms inclusive areprepared in the same manner from the appropriate different lower-alkoxystarting material. Moreover, when one di- 'lower-alkylamino group, suchas the dimethylamino group, is present in a compound, otherdilower-alkylamino compounds are prepared in the same manner startingonly with the selected dilferent dilower-alkylamino compound. In thesame manner, ortho and meta products are produced instead of the para byutilizing the selected ortho or meta substituted starting material, andvice versa. Similarly other molecular changes within the scope of theinvention are readily made.

Formulation and Administration.Effective quantities of any of theforegoing pharmacologically active compounds may be administered to aliving animal body in any one of various ways, for example, orally as incapsules or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The :free basic amino compounds, while effective, arepreferably formulated and administered in the form of their non-toxicacid-addition or quaternary ammonium salts for purposes of convenienceof crystallization, increased solubility, and the like.

Although very small quantities of the active materials of the presentinvention, even as low as 0.1 milligram, are effective when minortherapy is involved or in cases of administration to subjects having arelatively low body weight, unit dosages are usually five milligrams orabove and preferably twenty-five, fifty or one-hundred milligrams oreven higher, depending of course upon the emergency of the situation andthe particular result, e.g., analeptio or hypotensive, desired. Five tofifty milligrams appears optimum per unit dose, while usual broaderranges appear to be one to 100 milligrams per unit dose. The activeagents of the invention may be combined with other pharmacologicallyactive agents, or with buffers, antacids or the like, for administrationand the proportion of the active agent in the compositions may be variedwidely. It is only necessary that the active ingredient constitute aneffective amount, i.e., such that a suitable effective dosage will beobtained consistent with the dosage form employed. Obviously, severalunit dosage forms may be administered at about the same time. The exactindividual dosages as well as daily dosages in a particular case will ofcourse be determined according to established medical principles.

The fourmulations of Example 35 are representative for thepharmacologically active compounds of the invention, but have beenespecially designed to embody as active ingredient1-loweralkyl-3-phenyl-4-(beta-chloroethyl)-2-imidazolidinones or thecorresponding 4-(betaaminoethyl) compounds, especially thedilower-alkylaminoethyl or heterocyclic aminoethyl compounds, or theirhydrochlorides, hydrobromides, methiodides, or like phar-maceuticallyacceptable salts.

amounts of active ingredient, reduction may be made in the amount oflactose.

Typical blend for encapsulation: Per capsule, mg.

Active ingredient, as salt 5.0 Lactose 296.7 Starch 129.0 Magnesiumstearate 4.3 Total 435.0

Additional capsule formulations preferably contain a higher dosage ofactive ingredient and are as follows:

Ingredients mg. per 250 mg. per 500 mg. per

capsule capsule capsule Active Ingredient, as salt 100.0 250.0 500. 0Lactose 231. 5 126. 5 31. 1 Starch 99. 2 54. 2 13. 4 Magnesium stearate4. 3 4. 3 5. 5

Total, mg 435. 0 435. 0 550. 0

In each case, uniformly blend the selected active ingredient withlactose, starch, and magnesium stearate and encapsulate the blend.

2 TABLETS A typical formulation for a tablet containing 5.0 mg. ofactive ingredient per tablet follows. The formulation may be used forother strengths of active ingredient by adjustment of weight ofdicalcium phosphate.

Per tablet, mg.

(1) Active ingredient 5.0 (2) Corn starch 13.6 (3) Corn starch (paste)3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate0.9

(A) 50 mg. TABLET Ingredients: Per tablet, mg. Active ingredient, assalt 50.0 Lactose 90.0 Milo starch 20.0 Corn starch 38.0 Calciumstearate 2.0

Total 200.0

Uniformly blend the active ingredient, lactose, milo starch and cornstarch. This blend is granulated using water as a granulating medium.The wet granules are passed through an eight mesh screen and dried at todegrees Fahrenheit overnight. The dried granules are passed through anumber ten mesh screen and blended with the proper amount of calciumstearate and this blend is then converted into tablets on a suitabletablet press.

(B) '100 mg. TABLET Ingredients: Per tablet, mg. Active ingredient, assalt 100.0 Lactose 190.0 Dicalcium phosphate 172.2 Starch 54.0 Milostarch 21.6 Calcium stearate 2.2

Total 540.0

Uniformly blend the active ingredient, lactose dicalcium phosphate,starch and milo starch. This blend is granulated with water and the wetmass is passed through a number eight mesh screen. The wet granules aredried at 140-160 degrees Fahrenheit overnight. The dried granules arepassed through a number ten mesh screen. These dried granules areblended with the proper weight of calcium stearate and the lubricatedgranules are then converted into tablets on a suitable tablet press.

(C) 250 mg. TABLET Ingredients: Per tablet, mg. Active ingredient, assalt 500.0 Corn starch 56.0 Carbowax 6000 (polyethylene glycol of M.W.

approximately 6000) 25.0 Lactose 35.0 Magnesium stearate 4.0

Total 370.0

Uniformly blend the active ingredient, corn starch, Carbowax 6000,lactose, and one-half the weight of magnesium stearate required. Thisblend is then sluggcd on a suitable tablet press. These slugs aregranulated through a ten mesh screen on an oscillating granulator. Thesegranules are then blended with the remainder of the magnesium stearateand the lubricated granules are then converted into tablets on asuitable tablet press.

(D) 500 mg. TABLET Ingredients: Per tablet, mg. Active ingredient, assalt 500.0

Corn starch (wet) 86.4 Milo starch 32.4 Calcium stearate 3.2 Corn starch(dry) 26.0

Total 648.0

Uniformly blend the active ingredient, corn starch and milo starch. Thisblend is wet granulated using water and the wet mass is passed through anumber eight mesh screen. These wet granules are dried overnight at140-160 degrees Fahrenheit. The dried granules are passed through anumber ten mesh screen. The dried granules and weighed amounts of cornstarch and calcium stearate are uniformly blended and these lubricatedgranules are compressed on a suitable tablet press.

(3) INJECTABLE2% STERILE SOLUTION Per cc.

Active ingredient mg 20 Preservative, e.g., chlorobutanol, percentweight/ volume 0.5

Water for injection, q.s.

Prepare solution, clarify by filtration, fill into vials, seal, andautoclave.

(4) The pharmacologically active compounds provided by the presentinvention may also be administered successfully by embodying aneffective quantity thereof in an injectable suspension for injectioninto an animal body, in oral powders, suspensions or syrups, and inother acceptable dosage forms.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made in the compounds, compositions, methods, andprocedures of the present invention without departing from the spirit orscope thereof, and it is therefore to be understood that the inventionis to be limited only by the scope of the appended claims.

24 We claim: 1. A 1,3-clisubstituted4-(2-substituted-ethyl)-2-imidazolidinone having the formula:

wherein R is selected from the group consisting of lower-alkyl,lower-alkenyl, phenyllower-alkyl, cycloalkyl having a maximum of 9carbon atoms, and cycloalkenyl having a maximum of 9 carbon atoms,wherein R is selected from the group consisting of phenyl, loweralkylphenyl, dilower alkylphenyl, lower alkoxyphenyl, halophenyl,trifiuoromethylphenyl, lower-alkyl-halo-phenyl,lower-alkylmercaptophenyl, dilower-alkylaminophenyl, and naphthyl, andwherein Y is selected from the group consisting of CN, COOR', CONHCONHR", where in R is loWer-alkyl, and CONR"R"' wherein NR"R' isN,N-dilower-alkylamino, and a saturated monocyclic heterocyclic radicalhaving up to a maximum of twelve carbon atoms selected from the groupconsisting of piperazino, piperidino, pyrrolidino, morpholino,thiomorpholino, and diloweralkylpiperazino. 2. A compound of claim 1which is a 1-lower-alkyl-3- phenyl-2-imidazolidinone-4-propionitrile.

3. A compound of claim 1 which is a lower-alkyl 1-lower-alkyl-3-phenyl-2-imidazolidinone-4-propionate.

4. A compound of claim 1 which is a 1-loWer-alkyl-3-phenyl-Z-imidazolidinone-4-propionamide.

5. A compound of claim 1 which is a 1-methyl-3-phenyl-2-imidazolidinone-4-propionitrile.

6. A compound of claim 1 which is 1-ethyl-3-phenyl-2-imidazolidinone-4-propionitrile.

7. A compound of claim 1 which is 1-isopropyl-3-phenyl-2-imidazolidinone-4-propionitrile.

References Cited UNITED STATES PATENTS 2,397,250 3/1946 Duschinsky260309.7 2,492,373 12/1949 Wood et al. 260309.7 2,512,512 6/ 1950 Wolfet al. 260-309] OTHER REFERENCES Dittmer et al.: Jour Biol. Chem, vol.164, pp. 19-28 (1946).

Henze et al.: Chem. Abst., vol. 44, column 1972 (1950).

Kleev et al.: Zhur. Obshchei Khim, vol. 31, pp. 2595-9 (1961).

McKennis et al.: Jour. Amer. Chem. Soc., vol. 68, pp. 832-5 (1946).

HENRY R. JILES, Primary Examiner.

NATALIE TROUSOF, Assistant Examin r.

U.S. C1.X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,429,893 February 25 1969 Carl D. Lunsford et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 4 line 27 "chlorobenzy" should read chlorobenzyl Columns 7 and 8TABLE' 1, seventh column, line 9 thereof, "Fumarate 612-l63 C. shouldread Fumarate l62l63 C. Column 13, lines 32 and 33,"-l-allyl3phenyl2imidazolidinone by reacting l-allyl3-anilinopyrrolidine'34 (4" should read -l methyl-3-(4-dimethy1aminophenyl)2imidazolidinoneby reacting lmethyl-3 (4- line 38 "4- (3-" should read 4- (2- Column 20line 47 "morpholinothyl) -lisopropyl-3- (2- ,4-" should readmorpholinoethyl-lisopropyl3 (2 ,4- Column 23, line 3 "500 0" should read250 0 Signed and sealed this 3rd day of March 1970 (SEAL) Attest:

Edward M. Fletcher, Jr. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents

